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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 12 April 2011, Vol.108(15), pp.6211-6
    Description: Invariant natural killer T cells (iNKT cells) are innate-like T cells important in immune regulation, antimicrobial protection, and anti-tumor responses. They express semi-invariant T cell receptors, which recognize glycolipid antigens. Their positive selection is mediated by double-positive (DP) thymocytes, which present glycolipid self-antigens through the noncanonical MHC class I-like molecule CD1d. Here we provide genetic and biochemical evidence that removal of the transcription factor Bcl11b in DP thymocytes leads to an early block in iNKT cell development, caused by both iNKT cell extrinsic and intrinsic defects. Specifically, Bcl11b-deficient DP thymocytes failed to support Bcl11b-sufficient iNKT precursor development due to defective glycolipid self-antigen presentation, and showed enlarged lysosomes and accumulation of glycosphingolipids. Expression of genes encoding lysosomal proteins with roles in sphingolipid metabolism and glycolipid presentation was found to be altered in Bcl11b-deficient DP thymocytes. These include cathepsins and Niemann-Pick disease type A, B, and C genes. Thus, Bcl11b plays a central role in presentation of glycolipid self-antigens by DP thymocytes, and regulates directly or indirectly expression of lysosomal genes, exerting a critical extrinsic role in development of iNKT lineage, in addition to the intrinsic role in iNKT precursors. These studies demonstrate a unique and previously undescribed role of Bcl11b in DP thymocytes, in addition to the critical function in positive selection of conventional CD4 and CD8 single-positive thymocytes.
    Keywords: Antigen Presentation -- Genetics ; Autoantigens -- Immunology ; Glycolipids -- Immunology ; Natural Killer T-Cells -- Immunology ; Repressor Proteins -- Metabolism ; T-Lymphocytes -- Immunology ; Tumor Suppressor Proteins -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 05 April 2016, Vol.113(14), pp.E2057-65
    Description: Mutations in SMAD4 predispose to the development of gastrointestinal cancer, which is the third leading cause of cancer-related deaths. To identify genes driving gastric cancer (GC) development, we performed a Sleeping Beauty (SB) transposon mutagenesis screen in the stomach of Smad4(+/-) mutant mice. This screen identified 59 candidate GC trunk drivers and a much larger number of candidate GC progression genes. Strikingly, 22 SB-identified trunk drivers are known or candidate cancer genes, whereas four SB-identified trunk drivers, including PTEN, SMAD4, RNF43, and NF1, are known human GC trunk drivers. Similar to human GC, pathway analyses identified WNT, TGF-β, and PI3K-PTEN signaling, ubiquitin-mediated proteolysis, adherens junctions, and RNA degradation in addition to genes involved in chromatin modification and organization as highly deregulated pathways in GC. Comparative oncogenomic filtering of the complete list of SB-identified genes showed that they are highly enriched for genes mutated in human GC and identified many candidate human GC genes. Finally, by comparing our complete list of SB-identified genes against the list of mutated genes identified in five large-scale human GC sequencing studies, we identified LDL receptor-related protein 1B (LRP1B) as a previously unidentified human candidate GC tumor suppressor gene. In LRP1B, 129 mutations were found in 462 human GC samples sequenced, and LRP1B is one of the top 10 most deleted genes identified in a panel of 3,312 human cancers. SB mutagenesis has, thus, helped to catalog the cooperative molecular mechanisms driving SMAD4-induced GC growth and discover genes with potential clinical importance in human GC.
    Keywords: SB Mutagenesis ; Smad4-Cooperating Genes ; Gastric Cancer ; Mutagenesis ; DNA Transposable Elements -- Genetics ; Smad4 Protein -- Genetics ; Stomach Neoplasms -- Genetics ; Transposases -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 31 July 2012, Vol.109(31), pp.E2101-9
    Description: Mammalian pigmentation is driven by the intercellular transfer of pigment-containing melanosomes from the tips of melanocyte dendrites to surrounding keratinocytes. Tip accumulation of melanosomes requires myosin Va, because melanosomes concentrate in the center of melanocytes from myosin Va-null (dilute) mice. This distribution defect results in inefficient melanosome transfer and a dilution of coat color. Dilute mice that simultaneously lack melanoregulin, the product of the dilute suppressor locus, exhibit a nearly complete restoration of coat color, but, surprisingly, melanosomes remain concentrated in the center of their melanocytes. Here we show that dilute/dsu melanocytes, but not dilute melanocytes, readily transfer the melanosomes concentrated in their center to surrounding keratinocytes in situ. Using time-lapse imaging of WT melanocyte/keratinocyte cocultures in which the plasma membranes of the two cells are marked with different colors, we define an intercellular melanosome transfer pathway that involves the shedding by the melanocyte of melanosome-rich packages, which subsequently are phagocytosed by the keratinocyte. Shedding, which occurs primarily at dendritic tips but also from more central regions, involves adhesion to the keratinocyte, thinning behind the forming package, and apparent self-abscission. Finally, we show that shedding from the cell center is sixfold more frequent in cultured dilute/dsu melanocytes than in dilute melanocytes, consistent with the in situ data. Together, these results explain how dsu restores the coat color of dilute mice without restoring intracellular melanosome distribution, indicate that melanoregulin is a negative regulator of melanosome transfer, and provide insight into the mechanism of intercellular melanosome transfer.
    Keywords: Carrier Proteins -- Metabolism ; Keratinocytes -- Metabolism ; Melanocytes -- Metabolism ; Melanosomes -- Metabolism ; Skin Pigmentation -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 25 January 2011, Vol.108(4), pp.1531-1536
    Description: DNA transposons have been widely used for transgenesis and insertional mutagenesis in various organisms. Among the transposons active in mammalian cells, the moth-derived transposon piggyBac is most promising with its highly efficient transposition, large cargo capacity, and precise repair of the donor site. Here we report the generation of a hyperactive piggyBac transposase. The active transposition of piggyBac in multiple organisms allowed us to screen a transposase mutant library in yeast for hyperactive mutants and then to test candidates in mouse ES cells. We isolated 18 hyperactive mutants in yeast, among which five were also hyperactive in mammalian cells. By combining all mutations, a total of 7 aa substitutions, into a single reading frame, we generated a unique hyperactive piggyBac transposase with 17-fold and ninefold increases in excision and integration, respectively. We showed its applicability by demonstrating an increased efficiency of generation of transgene-free mouse induced pluripotent stem cells. We also analyzed whether this hyperactive piggyBac transposase affects the genomic integrity of the host cells. The frequency of footprints left by the hyperactive piggyBac transposase was as low as WT transposase (~1%) and we found no evidence that the expression of the transposase affects genomic integrity. This hyperactive piggyBac transposase expands the utility of the piggyBac transposon for applications in mammalian genetics and gene therapy.
    Keywords: Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Mycology ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Genetics ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Cytology
    ISSN: 00278424
    E-ISSN: 10916490
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, April 9, 2013, Vol.110(15), p.6091(6)
    Description: To define genetic lesions driving leukemia, we targeted credependent Sleeping Beauty (SB) transposon mutagenesis to the blood-forming system using a hematopoietic-selective vav 1 oncogene (vav1) promoter. Leukemias of diverse lineages ensued, most commonly lymphoid leukemia and erythroleukemia. The inclusion of a transgenic allele of Janus kinase 2 (JAK2)V617F resulted in acceleration of transposon-driven disease and strong selection for erythroleukemic pathology with transformation of bipotential erythro-megakaryocytic cells. The genes encoding the E-twenty-six (ETS) transcription factors Ets related gene (Erg) and Etsl were the most common sites for transposon insertion in SB-induced JAK2V617F-positive erythroleukemias, present in 87.5% and 65%, respectively, of independent leukemias examined. The role of activated Erg was validated by reproducing erythroleukemic pathology in mice transplanted with fetal liver cells expressing translocated in liposarcoma (TLS)-ERG, an activated form of ERG found in human leukemia. Via application of SB mutagenesis to TLS-ERG-induced erythroid transformation, we identified multiple loci as likely collaborators with activation of Erg. Jak2 was identified as a common transposon insertion site in TLS-ERG-induced disease, strongly validating the cooperation between JAK2V617F and transposon insertion at the Erg locus in the JAK2V617F-positive leukemias. Moreover, loci expressing other regulators of signal transduction pathways were conspicuous among the common transposon insertion sites in TLS-ERG-driven leukemia, suggesting that a key mechanism in erythroleukemia may be the collaboration of lesions disturbing erythroid maturation, most notably in genes of the ETS family, with mutations that reduce dependence on exogenous signals. www.pnas.org/cgi/doi/10.1073/pnas.1304234110
    Keywords: Transposons -- Physiological Aspects ; Transposons -- Health Aspects ; Mutagenesis -- Research ; Transcription Factors -- Physiological Aspects ; Transcription Factors -- Health Aspects ; Leukemia -- Physiological Aspects ; Leukemia -- Genetic Aspects ; Cancer Genetics -- Research
    ISSN: 0027-8424
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  • 6
    Language: English
    In: Cancer Research, 08/01/2015, Vol.75(15 Supplement), pp.3932-3932
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 7
    Language: English
    In: Cancer Research, 07/15/2012, Vol.72(14 Supplement), pp.B9-B9
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 30 July 2013, Vol.110(31), pp.E2885-94
    Description: Ecotropic viral integration site-1 (EVI1) is an oncogenic zinc finger transcription factor whose expression is frequently up-regulated in myeloid leukemia and epithelial cancers. To better understand the mechanisms underlying EVI1-associated disease, we sought to define the EVI1 interactome in cancer cells. By using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics, we could confidently assign 78 proteins as EVI1-interacting partners for FLAG-tagged EVI1. Subsequently, we showed that 22 of 27 tested interacting proteins could coimmunoprecipitate with endogenous EVI1 protein, which represented an 81.5% validation rate. Additionally, by comparing the stable isotope labeling by amino acids in cell culture (SILAC) data with high-throughput yeast two hybrid results, we showed that five of these proteins interacted directly with EVI1. Functional classification of EVI1-interacting proteins revealed associations with cellular transcription machinery; modulators of transcription; components of WNT, TGF-β, and RAS pathways; and proteins regulating DNA repair, recombination, and mitosis. We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. Collectively, these combinatorial proteomic approaches demonstrate that EVI1 interacts with large and complex networks of proteins, which integrate signals from various different signaling pathways important for oncogenesis. Comprehensive analysis of the EVI1 interactome has thus provided an important resource for dissecting the molecular mechanisms of EVI1-associated disease.
    Keywords: Evi1 Complex Locus Mass Spectrometry ; Mds1 ; Mitosis ; Recombinational DNA Repair ; Wnt Signaling Pathway ; DNA-Binding Proteins -- Metabolism ; Neoplasms -- Metabolism ; Oncogene Proteins -- Metabolism ; Transcription Factors -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: Science (New York, N.Y.), 16 January 2004, Vol.303(5656), pp.333
    Description: In a milestone study describing the first "cure" of a genetic disease by retroviral gene therapy, nine out of ten infants born with X-linked severe combined immunodeficiency were successfully treated. Unfortunately, almost three years after the therapy was completed, two of the children developed T cell leukemia, which was considered as extremely rare. To address the serious concerns regarding the future of human gene therapy trials, Dave et al provide a genetic explanation for the high frequency of leukemia in these gene therapy trials.
    Keywords: Genetic Therapy ; Mutagenesis, Insertional ; DNA-Binding Proteins -- Genetics ; Leukemia, T-Cell -- Genetics ; Metalloproteins -- Genetics ; Receptors, Interleukin-2 -- Genetics ; Retroviridae -- Genetics
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 10
    Language: English
    In: Science (New York, N.Y.), 02 July 2010, Vol.329(5987), pp.85-9
    Description: T cells develop in the thymus and are critical for adaptive immunity. Natural killer (NK) lymphocytes constitute an essential component of the innate immune system in tumor surveillance, reproduction, and defense against microbes and viruses. Here, we show that the transcription factor Bcl11b was expressed in all T cell compartments and was indispensable for T lineage development. When Bcl11b was deleted, T cells from all developmental stages acquired NK cell properties and concomitantly lost or decreased T cell-associated gene expression. These induced T-to-natural killer (ITNK) cells, which were morphologically and genetically similar to conventional NK cells, killed tumor cells in vitro, and effectively prevented tumor metastasis in vivo. Therefore, ITNKs may represent a new cell source for cell-based therapies.
    Keywords: Cell Lineage ; Lymphopoiesis ; Killer Cells, Natural -- Physiology ; Repressor Proteins -- Genetics ; T-Lymphocytes -- Physiology ; Tumor Suppressor Proteins -- Genetics
    ISSN: 00368075
    E-ISSN: 1095-9203
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